Armin de Meijere

Isocyanides in the Synthesis of Nitrogen Heterocycles

Isocyanides have long proved themselves to be irreplaceable building blocks in modern organic chemistry. The unique features of the isocyano group make isocyanides particularly useful for the synthesis of a number of important classes of nitrogen heterocycles, such as pyrroles, indoles, and quinolines. Several cocyclizations of isocyanides via zwitterions and radical intermediates as well as transition-metal-catalyzed syntheses of different types of heterocycles have recently been developed. Methods starting from isocyanides often have distinct advantages over alternative approaches to the same heterocycles because of their enhanced convergence, the great simplicity of most of the operations with them, and the great variety of isocyanides readily available for use. Isocyanides have also been used in some enantioselective syntheses of chiral heterocyclic compounds, including natural products as well as precursors thereof.

Fischer Carbene Complexes as Chemical Multitalents: The Incredible Range of Products from Carbenepentacarbonylmetalα,β-Unsaturated Complexes

The metal carbene complexes, discovered by E. O. Fischer at the start of the 1960s and carrying his name, have since proved themselves to be irreplaceable building blocks for organic synthesis. In particular, since the discovery of the Dötz reaction, a formal cycloaddition of Fischer alpha,beta-unsaturated carbene complexes to alkynes with CO insertion, this area of chemistry has become increasingly interesting to organic chemists. In spite of the considerable diversity of reactions performed with these complexes, proper selection of substrates and careful adjustment of the reaction conditions have allowed, in most cases the perfectly selective preparation of individual compounds of this enormous range of products. The spectrum of new successes begins with the conventional Diels-Alder reaction of alkynylcarbene complexes and the formal regioselective [3+2] cycloaddition of alkenylcarbene complexes to alkynes. It extends much further, however, from cascade reactions with the formation of oligofunctional and oligocyclic products of impressive molecular complexity to complex, formal [3+6] cocyclizations in which six bonds are formed in a single operational step. Beyond doubt, the methodological arsenal of preparative organic chemistry cannot be imagined any more without the valuable transformations of the Fischer carbene complexes; it only remains to be seen whether one or other of the numerous new types of cocyclization products of these complexes can establish itself as a lead structure in the search for biologically active compounds.

Palladium in action: domino coupling and allylic substitution reactions for the efficient construction of complex organic molecules☆

Abstract The palladium-catalyzed arylation and alkenylation of alkenes, generally called the Heck reaction, has been applied to a number of new concepts. Starting from simple, oligohalogenated alkenes and arenes, the synthesis of a variety of highly functionalized carbon skeletons has been established. The domino-type combination of an intramolecular Heck with an inter- or intramolecular Diels–Alder reaction has been shown to provide facile access to interesting bicyclic and tetracyclic frameworks. While intramolecular Heck reactions on trisubstituted, cyclopropylidene-terminated alkenes proceeded with retention of the cyclopropyl moiety, tetrasubstituted alkenes with methylenecyclopropane end groups reacted with ring opening to yield cross-conjugated trienes. The study of the palladium-catalyzed oligocyclizations of 2-bromoalka-1,(ω-1)-diene-n-ynes has revealed interesting and useful systematics as to achievable ring size combinations and skeletal types. Highly functionalized methylenecyclopropanes are conveniently accessible via palladium-catalyzed allylic substitution reactions of 1-ethenylcyclopropyl sulfonates and chlorides as well as cyclopropylideneethyl esters which proceed with complete regioselectivity in most cases.

Bicyclopropylidene — A Unique Tetrasubstituted Alkene and a Versatile C6-Building Block

Strain in an organic molecule often correlates with increased reactivity, at least for certain types of reactions. Thus, the elucidation of the chemistry of highly strained alkenes like the unusual tetrasubstituted alkene, bicyclopropylidene (1), which is a particularly strained derivative of methylenecyclopropane (2), has proved to be fruitful both with respect to synthetic applications as a C6 building block, as well as understanding certain reaction principles. The different, steadily improved methods which have been developed for the preparation of this unusual alkene in the last thirty years as well as rather recent methods for the synthesis of functionally substituted, and spirocyclopropanated derivatives as well as bis(bicyclopropylidenyls) are presented. The special aspects of molecular geometry in bicyclopropylidenes as well as strain and its influence on chemical properties are discussed.The rich chemistry of bicyclopropylidene beginning with its well-known thermal rearrangement and dimerization, its dihalocarbene additions all the way to its recently developed organometallic chemistry, especially its reactions under the catalysis of palladium and other transition metals, is covered. Finally, some synthetically useful chemical transformations of bicyclopropylidene derivatives, e.g., synthetic approaches to the cyclopropanated analogs of natural products, are presented.

Oligosubstituted Pyrroles Directly from Substituted Methyl Isocyanides and Acetylenes

The formal cycloaddition of alpha-metallated methyl isocyanides 1 onto the triple bond of electron-deficient acetylenes 2 represents a direct and convenient approach to oligosubstituted pyrroles 3. The scope and limitations of this reaction (24 examples, 25-97% yield) are reported along with an optimization of the reaction conditions and a rationalization of the mechanism. In addition, a related newly developed Cu(I)-mediated synthesis of 2,3-disubstituted pyrroles by the reaction of copper acetylides derived from unactivated terminal alkynes with substituted methyl isocyanides is described (11 examples, 5-88% yield).

Fischer-Carbenkomplexe als chemische Multitalente: die unglaubliche Produktpalette ausα,β-ungesättigten Carbenpentacarbonylmetall-Komplexen

Die von E. O. Fischer Anfang der sechziger Jahre erstmals isolierten und nach ihm benannten Carbenmetall-Komplexe haben sich mittlerweile als unentbehrliche Synthesebausteine erwiesen. Insbesondere seit der Entdeckung der Dotz-Reaktion, einer formalen Cycloaddition von α,β-ungesattigten Fischer-Carbenkomplexen an Alkine unter CO-Insertion, hat diese Chemie auch bei Organikern an Interesse gewonnen. Trotz der enormen Reaktionsvielfalt dieser Komplexe lassen sich durch geschickte Auswahl der Substrate und sorgfaltige Anpassung der Reaktionsbedingungen einzelne Verbindungen der riesigen Produktpalette jeweils selektiv gewinnen. Das Spektrum der Erfolge beginnt mit herkommlichen Diels-Alder-Reaktionen von Alkinylcarben-Komplexen und regioselektiven formalen [3+2]-Cycloadditionen von Alkenylcarben-Komplexen an Alkine. Es reicht allerdings viel weiter – uber Kaskadenreaktionen unter Bildung von oligofunktionellen und oligocyclischen Produkten von beeindruckender Molekulkomplexitat bis zu komplizierten formalen [3+6]-Cocyclisierungen, bei denen sechs Bindungen in einem Verfahrensschritt geknupft werden. Zweifellos lassen sich schon heute die Transformationen der Fischer-Carbenkomplexe aus dem Methodenarsenal der praparativen Organischen Chemie nicht mehr wegdenken; abzuwarten bleibt lediglich, ob sich das eine oder andere der vielfaltigen Cocyclisierungsprodukte dieser Komplexe als Leitstruktur in der Wirkstoff-Forschung etablieren kann.

New Efficient Multicomponent Reactions with C−C Coupling for Combinatorial Application in Liquid and on Solid Phase

Up to nine C-C bonds are formed selectively from up to seven components starting from an alkene, a haloarene, and a dienophile [Eq. (1)]. A comparison of liquid- and solid-phase reactions reveals a surprising superiority of the solid-phase reaction.

An Evolving Multifunctional Molecular Building Block: Bicyclopropylidene

The elucidation of the chemistry of the highly strained and unusually tetrasubstituted alkene bicyclopropylidene (2), has proved to be fruitful, both with respect to synthetic applications as a multifunctional C6 building block and for the understanding of certain reaction principles. The different, and steadily improved, methods developed over the last thirty years for the preparation of this unusual alkene, and the more recent methods for the synthesis of functionally substituted as well as spirocyclopropanated derivatives, are presented. The rich chemistry of bicyclopropylidene, beginning with its well-known thermal rearrangement and dimerization, its [2+n] cycloadditions with various carbenes, alkenes, 1,3-dipoles, and dienes all the way to its recently developed organometallic chemistry, especially its reactions under the catalysis of palladium and other transition metals, is covered. Some of the peculiar physical properties of bicyclopropylidene (2) which explain its unique reactivity, are also discussed. Finally, some synthetically useful chemical transformations of bicyclopropylidene derivatives, for example, synthetic approaches to certain cyclopropanated analogs of natural products, are presented.

New cascade and multiple cross-coupling reactions for the efficient construction of complex molecules

Multiple palladium-catalyzed cross-coupling reactions of the Heck, Suzuki and Stille types on oligofunctionalized cycloalkenes and arenes can be performed in very high yields. While Heck type reactions on 1,2-dibromocycloalkenes or 2-bromocyclohexenyl triflates lead only to the twofold coupling products, the Stille coupling of the latter substrates occurs chemoselectively at the site of the triflate leaving group to give bromobutadienes which readily undergo subsequent Heck reactions. The thus obtained 1,3,5-hexatrienes undergo thermal 6π-electrocyclizations to furnish bicyclic skeletons, among others cyclohexenone-annelated systems after acidic work-up. Cascades of carbopalladation, rearrangement and [4+2] cycloaddition with bicyclopropylidene, aryl iodides and dienophiles constitute a new class of three-component reactions with a remarkable combinatorial potential, especially since they can be performed on the solid phase using the triazene linker. With nucleophiles instead of dienophiles yet another domino reaction consisting of carbopalladation, rearrangement and nucleophilic substitution can be performed with bicyclopropylidene, aryl or alkenyl iodides and C-, O- and N-centered nucleophiles to give a wide variety of interesting compounds. Under properly adjusted conditions even sixfold coupling reactions on hexabromoarenes can be achieved. When using Heck type reactions the initially formed intermediates en route to hexaalkenylarenes undergo intramolecular ring closures to yield multi-component mixtures of isomers of the expected products, but sixfold Stille and Suzuki couplings give pure hexaalkenylarenes in up to 73% yield. Crystal structure analyses reveal that depending on the nature of the alkenyl groups the six arms are positioned either on the same side of the central ring making it an interesting cup-shaped molecule or alternating above and below the central plane.

Palladium-catalyzed domino coupling reactions of aryl halides with norbornene and norbornene derivatives : a simple route to polycyclic aromatic compounds

Under palladium-catalysis, norbornene 1, dicyclopentadiene 10, norbornenol 13, and norbornenone 15 react with unsubstituted as well as substituted bromo- and iodobenzenes to give 1 : 3 coupling products with 4-aryl-9,10-dihydrophenanthrene units with up to 70% isolated yields. The structures of two such products 4a and 4e were proved by X-ray crystal structure analysis. 2-Bromothiophene 17 reacts with 1 and 10 to yield a mixture of 2 : 1 and 3 : 1 coupling products, while 3-iodopyridine 22a, 3-iodo-6-methylpyridine 22b and 4-iodopyridine 25 give only 2 : 1 coupling products with 5,6-dihydro-3,8-phenanthroline and 5,6-dihydro-2,9-phenanthroline units, respectively. Some new mechanistic insights into this interesting four-component domino coupling reaction are presented. The products can easily be transformed by photocyclization/dehydrogenation and/or flash vacuum pyrolysis to a variety of cyclopentadiene-anellated polycyclic aromatic compounds in very high yields. The reported sequence also presents the easiest access to benzo[e]pyrene.